Metastasis-Directed Radiotherapy Yields Durable Disease Control Without Systemic Therapy in Oligometastatic RCC

Radiotherapy administered without concurrent systemic therapy showed durable disease control and manageable toxicity in patients with oligometastatic clear cell renal cell carcinoma (RCC), according to findings from a phase 2 trial (NCT03575611) presented at the 2025 Kidney Cancer Research Summit.

With a median follow-up of 36.3 months (IQR, 26.5-51.1), the median progression-free survival (PFS) was 34.0 months (IQR, 28.3-54.1); the median systemic therapy-free survival (STFS) was 17.7 months (IQR, 14.9-22.4); and the 3-year overall survival (OS) was 86.5 months (IQR, 77.5%-92.1%).

The trial investigators noted that surveillance was associated with a median STFS of 14.9 months (95% CI, 10.6-25) in a phase 2 trial published in Lancet Oncology.²

At baseline, 60% of patients (n = 47/78) were minimal residual disease (MRD)-positive; among these patients, the median tumor fraction was 22.5 ppm. With 3 months of follow-up, 25% of patients who were MRD-positive at baseline converted to be MRD-negative.

Additionally, patients who were MRD negative demonstrated improved STFS vs those who were MRD positive since enrollment (HR, 2.75; 95% CI, 1.29-5.86; P = .006); since the 3-month MRD assessment, patients who were MRD negative were still favorable compared with those who were MRD positive (HR, 4.42; 95% CI, 2.06-9.5; P <.0001).

“Metastasis directed therapy without systemic therapy offers advantages in costs, toxicities, and clinic visits over frontline systemic therapies,” wrote presenting study author Chad Tang, MD, an associate professor in the department of Radiation Oncology, the department of Translational Molecular Pathology, and the department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, and coauthors.¹ “[Metastasis-directed therapy] without systemic therapy exhibited favorable OS and toxicity profiles. Biomarkers are needed at baseline to select patients and after [metastasis-directed therapy] to guide surveillance vs systemic therapy. Circulating tumor DNA (ctDNA) via a second-generation assay has the potential to inform both roles.”

The trial enrolled patients with oligometastatic RCC with clear cell histology, up to 5 metastases, and no prior systemic therapy, or more than 1 month off prior systemic therapy. Treatment consisted of receiving standard-of-care imaging plus standard-of-care biopsy, a correlative blood draw, then stereotactic radiation with or without surgical local therapy to all sites of disease, followed by standard-of-care imaging and correlative blood draw again. If patients experienced progression, they restarted the treatment cycle; otherwise, they started systemic therapy.

The trial’s co-primary end points were PFS per RECIST v1.1 and STFS, defined as a median STFS greater than 25 months.

It was noted that immunotherapy alone or as doublet, or tyrosine kinase inhibitor (TKI) costs around $150,000 to $300,000 per year, and stereotactic body radiation therapy costs around $15,000 to $40,000 per round; grade 3 or higher toxicities occur in 45% to 85% and 5% to 10%, respectively; and clinic visits happen at least monthly and for 1 to 2 visits per round.

Regarding safety, grade 2 or higher adverse events (AEs) were experienced by 20.8% of patients, grade 3 or higher AEs were experienced by 6.7%, and grade 3 toxicities were experienced by only 1 patient. The most common grade 2 AEs were musculoskeletal pain (n = 10), pneumonitis (n = 5), cough (n = 3), and dyspnea (n = 2); the most common grade 3 AEs were musculoskeletal pain (n = 5), leukocytosis (n = 2), pleural effusion (n = 1), and abdominal distension (n = 1); the only grade 4 AE was hyperglycemia (n = 1).

References

1. Tang C, Sherry A, Seo A, et al. Phase 2 trial of metastasis directed radiotherapy without systemic therapy (MRWS) for oligometastatic clear cell renal cell carcinoma (ccRCC) and investigation of circulating tumor DNA (ctDNA) as a personalized biomarker. Presented at the 2025 Kidney Cancer Research Summit; July 17, 2025; Boston, MA.
2. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17(9):1317-1324. doi:10.1016/S1470-2045(16)30196-6